Our previous study has demonstrated that Sle5, a lupus susceptibility interval identified in a murine lupus- prone model, NZM2410, can accelerate the development of systemic autoimmunity. Combination of Sle5 with Sle1, a genomic interval that mediates breach of immune tolerance to nuclear antigens, leads to early expansion of activated B and T cells, elevated levels of autoantibodies targeting broader spectrum of autoantigens, and the development of severe lupus nephritis. Zinc finger protein 296 (Zfp296) is a gene located in the Sle5 interval, and its product is predicted to have function as a transcription factor. We have found that additional phosphorylation sites are present in NZM2410 version of Zfp296 protein. Although the function of Zfp296 is still unknown, it is expressed at higher level in B and CD4 T lymphocytes. Over expression of Zfp296 in A20 B cell line inhibits anti-IgG induced NF-kappaB activation, an important pathway for cell survival. The goal of the proposed study is to identify the role of Zfp296 in controlling autoimmunity. We have two specific aims. First, we will determine the role of Zfp296 in regulating cell activation, proliferation and survival. We will examine the effects of Zfp296 overexpression or knockdown on antigen receptor- mediated cell activation, proliferation, and apoptosis. We will also determine the impact of Zfp296 polymorphism as seen in Sle5 on cell activation, proliferation and survival, by overexpressing Zfp296 of B6 allele and Sle5 allele to compare the difference in their ability to regulate cell activation, proliferation, and apoptosis. Second, we will determine whether Zfp296 overexpression can suppress autoimmunity in vivo. We will use overexpression of Zfp296 in vivo to determine the impact of B6 allele of Zfp296 on activities of B and CD4 T cells, and the development of autoimmunity in lupus mice. The outcomes of this study will provide us with knowledge of Zfp296 function in immune system, the role of its polymorphism in development of autoimmunity, and the potential of using Zfp296 overexpression as a therapeutic strategy for SLE. PUBLIC HEALTH RELEVANCE: The proposed study is to identify the role of a candidate lupus susceptibility gene on the development of autoimmunity. The outcome of this study should help to understand the role of its human counterpart in disease development and to develop a potential therapeutic for human lupus.